Clinical studies of human diabetic gastroparesis support the notion of autonomic neural dysfunction as a causative factor. Vagal nerve dysfunction has been documented in patients with diabetic gastropathy, but it is unclear whether this is an etiologic factor or an associated phenomenon. Although neuropeptides such as vasoactive intestinal polypeptide (VIP) and cholecystokinin (CCK) have been shown to influence neuromuscular transmission, the role of endocrine factors in the pathophysiology of diabetic gastroparesis has remained unexamined. The aim of this research proposal is to study the neural and endocrine controls of gastric emptying in experimental diabetes. The proposed investigations examine the influence of the duration of diabetes, the effects of hyperphagia and caloric malnutrition, and the influence of glycemic control with insulin on gastric emptying. Studies will determine whether the observed changes in gastric emptying are associated with altered gastric tissue levels of neuropeptides (VIP,CCK,neurotensin) or neuropeptide release. These studies examine the influence of the duration of the diabetic state on vagal and sciatic nerve concentrations of glucose, fructose, sorbitol, myoinositol, and Na+-K+-ATPase activity. Since the Principal Investigator's preliminary studies show that diabetes acutely reduces sciatic and vagus nerve Na+- K+-ATPase activities, experiments will examine the temporal effect of diabetes mellitus on the expression of 1) isoforms of Na+-K+-ATPase and 2) mRNA for the Na+-K+-ATPase isoforms in vagus and sciatic nerve. Studies will also examine whether identified abnormalities in diabetic vagus nerve can be improved by dietary myoinositol supplementation or aldose reductase inhibition in a manner similar to that observed in the diabetic sciatic nerve. These investigations will determine whether abnormalities in glucose metabolism and polyol pathway activity evident in diabetic peripheral nerve are also operant in the autonomic vagus nerve. In vitro studies will examine the influence of the vagus nerves and intrinsic nervous system on the compliance properties of the diabetic stomach as well as the influence of diabetes on distension-induced gastric neuropeptide release. Finally, a separate group of streptozotocin-treated diabetic rodents will undergo heterotopic pancreas transplantation to determine how well pancreas transplantation compares with conventional insulin treatment in preventing the complications of diabetes mellitus. It is anticipated that these studies will help define the neural mechanisms associated with diabetic gastropathy. Ultimately, the results of these investigations will improve not only the understanding of diabetic gastropathy, but also the treatment of patients with this disorder.